Inhibition of Fatty Acid Amide Hydrolase Alters Cortical CREB Signaling and Social Behavior in a Rat Model of Schizophrenia

Social withdrawal is a core negative symptom of schizophrenia and remains poorly understood at the molecular level. Dysregulation of the endocannabinoid system has been implicated in social behavior, yet its downstream signaling mechanisms are not fully characterized. In this context, this study examined the effects of the fatty acid amide hydrolase (FAAH) inhibitor, URB597, on CREB expression and its phosphorylation at serine 133 (pCREB) in saline-treated (1 mL/kg, i.p.) or phencyclidine-treated (PCP; 5 mg/kg, i.p., twice a day for 7 days) rats engaged in social interaction. CREB and pCREB expression was measured in six cortical regions selected for their established roles in social behavior: the prelimbic cortex (A32V), the cingulate cortex (A32D), the ventral orbital cortex (VO), the lateral orbital cortex (LO), the agranular insular cortex (AI), and the infralimbic cortex (A25). PCP-treated rats showed reduced social interaction, and URB597 reversed this deficit, whereas the same treatment decreased social interaction in saline controls. Across the six prefrontal and insular regions, CREB expression was largely unchanged, apart from a URB597-related reduction in the LO (main effect, p < 0.05) and an increase in the AI of PCP-treated rats. URB597 also reduced pCREB in VO (main effect, p < 0.05). In contrast, the AI showed clear group-specific effects: Both PCP-treated rats receiving vehicle and saline-treated rats receiving URB597 exhibited reduced pCREB relative to saline controls. Although URB597 did not significantly reverse the pCREB reduction in PCP-treated rats, pCREB levels in the AI positively correlated with time spent in social interaction (r = 0.43, p < 0.05). These findings identify the AI as a key neural substrate underlying social withdrawal in this model and suggest that targeting the endocannabinoid system within this region may represent a promising therapeutic strategy for alleviating the negative symptoms of schizophrenia.